Background: Surgical Site Infection (SSI) is defined as infection that occurring within 30 days after surgical procedure or within a year of implantation of prosthesis. Surgical Site Infection can happen in up to 30% of surgical procedures and records for up to 14% of Hospital Acquired Infection (HAIs). Aim of the Study: The aim of this study was to assess levels of nurse's Compliance; knowledge and practice regarding prevention of surgical site infection Guidelines and identify the barriers facing nurses' compliance with surgical site infection prevention Guidelines. Design: Cross sectional descriptive study design self-reported survey. Settings: Data was collected from surgical departments from selected Menoufia Governorate Hospitals, Egypt. Sample: A large convenience sample of 450 nurses was selected. Initially 600 questionnaires were distributed, of which only 400 returned completed, a response rate of 66.6%. Tools: was comprised of the: 1) Pre-designed structured questionnaire to assess nurses' socio-demographic characteristics' and Nurses' knowledge, 2) Likert-scale: to assess nurses' compliance, nurses' practice and nurses' barriers facing nurses with surgical site infection prevention guidelines. Study period: The study was conducted from July to November 2019 in the selected hospitals. Results: nurses' compliance mean scores were in low level with a mean of 13.01, it is clear that most of the nurses have poor knowledge, most of the nurses have poor practice about surgical site infection, concerning the most barriers of compliance facing nurses with surgical site infection prevention guidelines, were lack of a professional model, having no enough time, and some measures for the prevention of surgical site infection are not nurses' responsibilities. Conclusions: Nurses working in the surgical related wards reported a low level of knowledge, practice and compliance regarding the prevention of surgical site infection guidelines. The most barriers of compliance with surgical site infection prevention guidelines that reported by nurses were, lack of a professional model, nurses do not have enough time,